Image-forming MR methods which utilize the interaction between magnetic fields and nuclear spins in order to form two-dimensional or three-dimensional images are widely used nowadays, notably in the field of medical diagnostics, because for the imaging of soft tissue they are superior to other imaging methods in many respects, do not require ionizing radiation and are usually not invasive.
According to the MR method in general, the body of the patient to be examined is arranged in a strong, uniform magnetic field whose direction at the same time defines an axis (normally the z-axis) of the co-ordinate system on which the measurement is based. The magnetic field produces different energy levels for the individual nuclear spins in dependence on the magnetic field strength which can be excited (spin resonance) by application of an electromagnetic alternating field (RF field) of defined frequency (so-called Larmor frequency, or MR frequency). From a macroscopic point of view, the distribution of the individual nuclear spins produces an overall magnetization which can be deflected out of the state of equilibrium by application of an electromagnetic pulse of appropriate frequency (RF pulse) while the magnetic field of the RF pulse extends perpendicular to the z-axis, so that the magnetization performs a precession about the z-axis. This motion of the magnetization describes a surface of a cone whose angle of aperture is referred to as flip angle. The magnitude of the flip angle is dependent on the strength and the duration of the applied electromagnetic pulse. In the case of a so-called 90° pulse, the spins are deflected from the z axis to the transverse plane (flip angle 90°). The RF pulse is radiated toward the body of the patient via a RF coil arrangement of the MR device. The RF coil arrangement typically surrounds the examination volume in which the body of the patient is placed.
After termination of the RF pulse, the magnetization relaxes back to the original state of equilibrium, in which the magnetization in the z direction is built up again with a first time constant T1 (spin lattice or longitudinal relaxation time), and the magnetization in the direction perpendicular to the z direction relaxes with a second time constant T2 (spin-spin or transverse relaxation time). The variation of the magnetization can be detected by means of receiving RF coils which are arranged and oriented within the examination volume of the MR device in such a manner that the variation of the magnetization is measured in the direction perpendicular to the z-axis. The decay of the transverse magnetization is accompanied, after application of, for example, a 90° pulse, by a transition of the nuclear spins (induced by local magnetic field inhomogeneities) from an ordered state with the same phase to a state in which all phase angles are uniformly distributed (dephasing). The dephasing can be compensated by means of a refocusing pulse (for example a 180° pulse). This produces an echo signal (spin echo) in the receiving coils.
In order to realize spatial resolution in the body, linear magnetic field gradients extending along the three main axes are superposed on the uniform magnetic field, leading to a linear spatial dependency of the spin resonance frequency. The signal picked up in the receiving coils then contains components of different frequencies which can be associated with different locations in the body. The signal data obtained via the receiving coils corresponds to the spatial frequency domain and is called k-space data. The k-space data usually includes multiple lines acquired with different phase encoding. Each line is digitized by collecting a number of samples. A set of k-space data is converted to a MR image by means of Fourier transformation.
In some medical applications, the difference in MR signal intensity from standard MR protocols, i.e. the contrast, between different tissues might not be sufficient to obtain satisfactory clinical information. In this case, contrast enhancing techniques are applied, which rely for example on advanced MR sequences or on MR contrast agents, like paramagnetic agents (Gd-DTPA/DOTA), or combinations of both. In a number of important MR applications with or without using contrast agents, advanced contrast enhancing MR sequences are favorable, which employ long RF pulses or quasi continuous-wave RF transmission for e.g. saturation transfer, hetero- or homonuclear polarization transfer, proton decoupling or spin locking.
A particularly promising approach for contrast enhancement and increase of MR detection sensitivity (by orders of magnitude) is the known method based on ‘Chemical Exchange Saturation Transfer’ (CEST), as initially described by Balaban et al. (see e.g. U.S. Pat. No. 6,962,769 B1). With this CEST technique, the image contrast is obtained by altering the intensity of the water proton signal in the presence of a contrast agent with a fast-relaxing proton pool resonating at a slightly different frequency than the main water resonance. This is achieved by selectively saturating the nuclear magnetization of the pool of exchangeable protons which resonate at a frequency different from the water proton resonance. Exchangeable protons can be provided by exogenous CEST contrast agents (e.g. DIACEST, PARACEST or LIPOCEST agents), but can also be found in biological tissue (e.g. endogenous amide protons in proteins and peptides or protons in glucose, not covered in the original Balaban method). A frequency-selective saturation RF pulse that is matched to the MR frequency of the exchangeable protons is used for this purpose. The saturation of the MR signal of the exchangeable protons is subsequently transferred to the MR signal of nearby water protons within the body of the examined patient by (chemical or physical) exchange with the water protons, thereby decreasing the water proton MR signal. The selective saturation at the MR frequency of the exchangeable protons thus gives rise to a negative contrast in a proton-density weighted MR image. Amide proton transfer (APT) MR imaging of endogenous exchangeable protons allows highly sensitive and specific detection of pathological processes on a molecular level, like increased protein concentrations in malignant tumor tissue. The APT signal is also sensitively reporting on locally altered pH levels—because the exchange rate is pH dependent—which can be e.g. used to characterize ischemic stroke. CEST contrast agents have several important advantages over T1- and T2-based MR contrast agents. CEST contrast agents allow for multiplexing by using a single compound or a mixture of compounds bearing exchangeable protons that can be addressed separately in a multi-frequency CEST MR examination. This is of particular interest for molecular imaging, where multiple biomarkers may be associated with several unique CEST frequencies. Moreover, the MR contrast in APT/CEST MR imaging can be turned on and off at will by means of the selective saturation RF pulse. Adjustable contrast enhancement is highly advantageous in many applications, for example when the selective uptake of the contrast agent in the diseased tissue in examined body is slow.
A problem of all known APT/CEST MR imaging techniques is that the selective saturation prior to the actual acquisition of image data takes a comparably long time. The build-up of the saturation of the exchangeable protons is a relatively slow process (the characteristic timescale is on the order of one second). Consequently, the desirable saturation period for APT/CEST measurements is typically 2-5 seconds. Then, immediately following the saturation period, a (slice-selective) excitation RF pulse is usually applied for generation of the bulk water MR signal and one or more MR signals are recorded, for example as gradient echoes or spin echoes. The acquisition of individual MR signals used for imaging takes typically only several milliseconds up to a few hundred milliseconds, wherein the full k-space is acquired as a set of these short signal acquisitions.
Since the APT/CEST technique is based on narrow-band off-resonance RF saturation of the exchangeable proton pool, significant average RF power, ideally a continuous-wave RF irradiation or RF pulse trains with high duty cycle, are required during several seconds prior to the actual MR signal acquisition. When implemented on MR imaging systems which are in clinical use at present, the APT/CEST detection sensitivity is disadvantageously suboptimal due to the hardware constraints of the standard RF power amplifiers commonly used in those systems. Such standard RF power amplifiers are designed to deliver high-power short RF pulses for imaging applications, wherein the maximum length of the RF pulses as well as the RF duty cycle are limited because of the heat dissipation within the electronics of the RF power amplifier. A typical solid-state RF power amplifier of MR imaging devices allows up to 250 ms of RF pulse duration with a RF duty cycle of 50%. This is not suitable for effective APT/CEST MR imaging which actually requires continuous-wave RF irradiation or pulse trains with a RF duty cycle of 70 to 100% over a time interval of 2-5 seconds for obtaining sufficient saturation of the proton magnetization, albeit at a lower RF power than required for the short RF pulses used for MR image-acquisition. Presently, saturation sequences are applied on clinical MR imaging systems with short RF saturation pulses of up to 800 ms only, as a result of the mentioned hardware constraints. This disadvantageously leads to a substantially reduced APT/CEST signal as compared to the CEST signal that could be obtained with optimal saturation.
A further disadvantage of the saturation sequences conventionally applied in APT/CEST MR imaging is that the ability to quantify the CEST effect may be compromised due to a spatially inhomogeneous saturation effect of the saturation RF pulse. A reason could be an imperfect homogeneity of the spatial distribution of the RF magnetic field (B1) during saturation. This is particularly a problem at high static magnetic field strength of 3 Tesla or more. The inhomogeneity of the B1-field results in non-linear distortions of the CEST signal intensity. A quantitative analysis of the CEST effect, which would be desirable for various applications, is difficult to achieve under such conditions.
Finally, it has to be mentioned that APT/CEST MR imaging is particularly constrained by the safety regulations for heat deposition (SAR) in the tissue of the examined patient because the long and powerful RF irradiation during saturation results in a considerable SAR contribution.